rs369191459

Positions:

chr2-27453455-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBP6

The NM_015662.3(IFT172):c.3880C>T(p.Arg1294Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

IFT172
NM_015662.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.87

Variant links:

Genes affected

IFT172 (HGNC:30391): (intraflagellar transport 172) This gene encodes a subunit of the intraflagellar transport subcomplex IFT-B. Subcomplexes IFT-A and IFT-B are necessary for ciliary assembly and maintenance. Mutations in this gene have been associated with skeletal ciliopathies, with or without polydactyly, such as such short-rib thoracic dysplasias 1, 9 or 10. [provided by RefSeq, Mar 2014]

IFT172 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

BP6

Variant 2-27453455-G-A is Benign according to our data. Variant chr2-27453455-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221925.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr2-27453455-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT172	NM_015662.3 linkuse as main transcript	c.3880C>T	p.Arg1294Cys	missense_variant	35/48	ENST00000260570.8	NP_056477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT172	ENST00000260570.8 linkuse as main transcript	c.3880C>T	p.Arg1294Cys	missense_variant	35/48	1	NM_015662.3	ENSP00000260570	P1	Q9UG01-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251460

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 10 with or without polydactyly;C4225342:Retinitis pigmentosa 71

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 221925). This variant has not been reported in the literature in individuals affected with IFT172-related conditions. This variant is present in population databases (rs369191459, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1294 of the IFT172 protein (p.Arg1294Cys). -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Anophthalmia-microphthalmia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.34

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.76

MVP

0.72

MPC

0.67

ClinPred

0.64

GERP RS

5.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.42

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over